Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Applicant' s amendment filed 01/15/2026 is acknowledged. Claims 74-76, 78-80, 84-87, 91, 95 have been amended. Claims 1-73, 77, and 81-82, 88-90, and 93-94 have been cancelled. Claims 74-76, 78-80, 83-87, 91-92, and 95 are pending in the instant application and the subject of this non-final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
Status of Prior Rejections/Objections:
The objections to claims 74, 89, and 91 are withdrawn in view of the amendments to or cancellation of the claims.
The 112(b) rejections to claim(s) 75-76, 78-80, 84-85, 88-90, and 95 is/are withdrawn in view of the amendments to or cancellation of the claims.
The 101 rejections of claims 74-76, 78-80, 83-87, 91-92, and 95 are maintained and modified in view of the amendments.
The prior art rejection(s) under 35 USC 102 directed to claim(s) 74-76, 78-80, 83, 91-92, and 95 as being anticipated by Abkevich (WO 2016/025958 A1) is/are maintained and modified as necessitated by claim amendments.
The prior art rejection(s) under 35 USC 103 directed to claim(s) 74-76, 78-80, 83-87, 91-92, and 95 are restated and modified as necessitated by claim amendments over corrected reference Abkevich (WO 2016/025958 A1).
The double patenting rejections are restated and modified as necessitated by claim amendments over corrected reference Abkevich (WO 2016/025958 A1). The rejection over 16/221165 has been updated to reflect the granting of US 12421555 B2.
New Ground(s) of Rejections
Claim Rejections - 35 USC § 112(b)
Claim 87 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 87, the claim recites “at least 5,000 polymorphic loci in at least 20 human … autosomes”. It is unclear if a total of 5000 loci are required across 20 human autosomes or if it is intended to require 5000 in each of the 20 autosomes. Thus, the metes and bounds of the claim are not clear or one of ordinary skill in the art.
Claim Rejections - 35 USC § 101
Claims 74-76, 78-80, 83-87, 91-92, and 95 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) abstract ideas and natural phenomenon. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, each claim is directed to a process.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
The claims are directed to a method of detecting homologous recombination (HR) deficiency status of a BRCA deficient, TNBC cell of a patient comprising sequencing DNA from a sample comprising the cell of the patient, detecting in the sequencing a combined number of regions, and detecting HR deficiency in the cell when the combined number of regions is greater than the selected threshold.
Detecting the regions and the HR deficiency encompass abstract ideas. Namely, detecting of regions encompasses the mental processes of observations/evaluations/judgments/opinions, e.g., visually looking at sequencing results and observing/evaluating it to identify the requisite regions, and/or calculations (including those that may be performed by the human mind), such as an algorithm to identify such regions. Likewise, the detecting HR deficiency encompasses mental processes and calculations (including those that may be done by the human mind), e.g., summing the number of detected regions and observing that it is greater than the threshold.
Additionally, the claims are directed to the natural phenomenon of the correlation between the number of LOH regions, TAI regions, and LST regions and homologous deficiency status of the sampled cell(s).
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 74, in addition to the abstract ideas addressed above, the claim recites sequencing DNA isolated from a sample. Sequencing, recited at a high level of generality, is well-understood, routine, and convention and not sufficient to integrate the judicial exceptions into a practical application, as it represents insignificant extra-solution activity. See MPEP 2105.06(d)(II), especially vii. Amplifying and sequencing nucleic acid sequences; MPEP 2106.05(g) regarding mere data gathering; and MPEP 2106.04 regarding insignificant extra-solution activity.
Regarding claims 75-6 and 78-80, the claims recite lengths/characteristics of regions. As such, they represent thresholds for the abstract ideas, and thus fail to integrate them into practical applications.
Regarding claims 83-87, the claims recite characteristics of the chromosomes and/or numbers of genomic loci sequenced/analyzed. Karakoc (Karakoc E, et al. Detection of structural variants and indels within exome data. Nat Methods. 2011 Dec 18;9(2):176-8) recites that whole exon sequencing is widespread and relevant to structural variant detection (para 1), wherein Marian (Marian AJ. Sequencing your genome: what does it mean? Methodist Debakey Cardiovasc J. 2014 Jan-Mar;10(1):3-6.) teaches that each exome comprises approximately 13,500 polymorphic loci (Abstract). It is noted that instant para [0094] also states whole exome sequencing may be used.
Samorodnitsky (Samorodnitsky E, et al. Comparison of custom capture for targeted next-generation DNA sequencing. J Mol Diagn. 2015 Jan;17(1):64-75.) teaches commercial targeted panels for SNV and copy number detection via sequencing (entire document, e.g., abstract and title) and that clinical laboratories use custom gene capture panels (para 1).
For this reason, sequencing a particular number of polymorphic loci on a particular set or subset of chromosomes is determined to be well-understood, routine and conventional, and thus fails to integrate the claim into a practical application. Such likewise amounts to selecting the data to be manipulated in the judicial exception(s). See MPEP 2106.05(g). As such, it amounts to extra-solution activity. See MPEP 2106.04(d). Likewise, the choice of the chromosomes in the abstract idea steps of detecting amounts to the same.
Regarding claims 91-92, the claims recite identifying the patient as likely to respond to a cancer treatment based on identifying the cancer cell as likely HRD. The claims fail to recite actual treatment steps, further encompassing mental processes, and thus do not integrate the claims into a practical limitation. See also MPEP 2106.04(d)(2): “If the limitation does not actually provide a treatment or prophylaxis…then it cannot integrate a judicial exception under the ‘treatment or prophylaxis’ consideration.”
Regarding claims 95, the claim recites that the combined number consists of the three types of regions. Thus, the limitation is directed to the calculation and thus fails to integrate the claim into a practical limitation.
Step 2B. Does the claim amount to significantly more?
Each of the limitations discussed in Step 2A encompasses an abstract idea, the selection of a particular type of data to use with the abstract idea, or a generically recited sequencing limitations that are well-known and routine utilized to furnish data for the abstract idea (i.e., insignificant extra-solution activity).
Further, the courts have found that analyzing DNA to provide sequence information or detect allelic variants (Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546) is well-understood, routine, and conventional activity. See also MPEP 2106.05(d).
As stated in MPEP2105.05(I), an inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). Even if the elements of the abstract ideas or the choice of the sample were found novel, the courts have been clear that such is insufficient to amount to significantly more. See, also, Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015) regarding a novel sample being insufficient to furnish “significantly more”.
Claim Rejections - 35 USC § 102
Claim(s) 74-76, 78-80, 83, 91-92 and 95 is/are rejected under 102(a)(1) and (a)(2) as being anticipated by Abkevich (WO 2016/025958 A1; published 02/18/2016).
Regarding claims 74 and 95, Abkevich teaches a method of determining an HRD status in a sample from a BRCA deficient, TNBC patient (entire document, e.g., para [0153]; Fig. 16; para [00349]: “line at 42 represents the HRD threshold between low [HRD] and high”; see para [00344-345]: “TNBC cohort…Fig. …distribution of HRD scores in the cohort”; para [00349]: “the distribution of HRD scores … as defined by BRCA mutation status [in the cohort]”; emphasis added), comprising:
sequencing DNA isolated from a sample comprising the TNBC cell of the patient (para [00293]: “sequencing on Illumina HiSeq2500”; para [00339]: “a capture panel which targets ~54,000 SNPs”…Allele counts from the sequencing…this panel”; para [00315-316]: “Illumina HiSeq2500…HRD Scores”)
detecting a combined number of LOH, TAI, and LST regions in at least one pair of human chromosomes (para [00344-355]: “HRD scores”; para [00342]: “The combined score (HRD score) was the summation of the LOH/TAI/LST scores”; instant claim 95; across the genome: para [00293]; [00153])
detecting deficiency when the number of LOH, TAI, and LAST regions is greater than 33 (para [00345]: “scores > 42 were considered to have high HRD…The bimodality illustrated in Figure 15 indicates that HRD scores effectively distinguished HR deficient and non-deficient states in the tumor”; see also Fig. 15 and Table 6, wherein this analysis inherently included BRCA deficient samples; also, para [00349]: “by BRCA mutation status…dotted line at 42 represents the HRD threshold”)
Abkevich applies the method to a cell of a sample (entire document, e.g., para [0045] and para [00153]).
It is noted that while sequencing isn’t explicitly stated in the TNBC cohort of Example 6, the same data types (regions data and BRCA status) and scores of Examples 4-5 (e.g., para [00314-315] and [00342]) were utilized. Thus, it is reasonable to conclude that the same data was inherently generated given the existence of the data in Example 6 and the absence of teaching of an alternative means of acquiring it.
It is noted that the range “greater than or equal to 42” anticipates “greater than 33”. See MPEP 2131.03.
Regarding claims 75-76, Abkevich teaches that the number of LOH regions >15 Mb in length but shorter than the length of the respective complete chromosome was used in calculating the HRD score (para [00342]).
Regarding claims 78-79, Abkevich teaches that number of TAI regions >11 Mb in length with allelic imbalance that extend to one of the subtelomeres, but do not cross the centromere was used in calculating the HRD score (para [00342]).
Regarding claim 80, Abkevich teaches that number of LST regions was the number of breakpoints between regions longer than 10 Mb (para [00342]). Abkevich teaches that the LSTs identified are somatic changes (para [0046] and [0048]: “LST refers to any somatic copy number…breakpoint”).
Regarding claim 83, by teaching that the method is performed using a panel that targets SNPs across the complete genome (para [00293]), Abkevich teaches that at least one pair of the human chromosomes are autosomes, given that only one pair of human chromosomes are sex chromosomes (see para [0002] or [0014]).
Regarding claims 91-92, Abkevich teaches predicting response of a patient to DNA damaging agent (see instant claim 92) cisplatin based on HR Deficiency status (para [00352]; Table 18; see also [00153] and para [00160]).
For at least these reasons, claims 74-76, 78-80, 83, 91-92 and 95 are anticipated by Abkevich.
Claim Rejections - 35 USC § 103
Claim(s) 74-76, 78-80, 83-87, 91-92, and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abkevich (WO 2016/025958 A1; published 02/18/2016).
Regarding claims 74 and 95, Abkevich teaches a method of determining an HRD status in a sample from a BRCA deficient, TNBC patient (entire document, e.g., para [0153]; Fig. 16; para [00349]: “line at 42 represents the HRD threshold between low [HRD] and high”; see para [00344-345]: “TNBC cohort…Fig. …distribution of HRD scores in the cohort”; para [00349]: “the distribution of HRD scores … as defined by BRCA mutation status [in the cohort]”; emphasis added), comprising:
sequencing DNA isolated from a sample comprising the TNBC cell of the patient (para [00293]: “sequencing on Illumina HiSeq2500”; para [00339]: “a capture panel which targets ~54,000 SNPs”…Allele counts from the sequencing…this panel”)
detecting a combined number of LOH, TAI, and LST regions in at least one pair of human chromosomes (para [00344-355]: “HRD scores”; para [00342]: “The combined score (HRD score) was the summation of the LOH/TAI/LST scores”; instant claim 95; across the genome: para [00293]; [00153])
detecting deficiency when the number of LOH, TAI, and LAST regions is greater than 33 (para [00345]: “scores > 42 were considered to have high HRD…The bimodality illustrated in Figure 15 indicates that HRD scores effectively distinguished HR deficient and non-deficient states in the tumor”; see also Fig. 15 and Table 6, wherein this analysis inherently included BRCA deficient samples; also, para [00349]: “by BRCA mutation status…dotted line at 42 represents the HRD threshold”)
Abkevich applies the method to a cell of a sample (entire document, e.g., para [0045] and para [00153]).
Additionally, while there is a single method of identifying the regions utilized in the cited example methods and it would be reasonable to conclude that the same methods of targeted sequencing were utilized with the TNBC cohort as with the previous cohorts, the TNBC cohort does not explicitly teach that the regions were identified in sequencing.
Abkevich teaches sequencing in the citations above and a variety of substitutable in para [0086].
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the data acquisition method in the embodiment, if for the sake of argument it were not sequencing, for sequencing, as such was an art recognized equivalents for the same purpose, as taught by Abkevich. See MPEP 2144.06(II). There would have been a strong expectation of success as they were known equivalents according to Abkevich, which teaches acquiring the relevant data.
It is noted that, while the threshold is taught by Abkevich, the threshold for the combined number of chromosomal aberrations is also matter of routine optimization. See MPEP 2144.05 and, for example, the teaching by Abkevich regarding utilizing different cutoffs for the LST component for BRCA1/2 intact and deficient samples based on ploidy (para [0049] and para [00298]).
Such is not found to be a critical feature of the instant invention at least because the instant specification defines BRCA deficient cells as inherently HR deficient (para [0093]: “deficient status for a pathway (e.g., HDR pathway) means at least one gene in the pathway … is deficient”, where in BRCA1 and BRCA2 are listed as HDR Pathway genes in Table 1 and HDR and HRD are defined as synonymous in para [0003]).
Further, para [0072] teaches a large range of suitable combined scores between 5 and 50, where >5 is identified as preferable and >42 most preferable. As such, the particular threshold chosen has not been identified to be critical to the invention.
Regarding claims 75-76, in the method of Abkevich, Abkevich teaches that the number of LOH regions >15 Mb in length but shorter than the length of the respective complete chromosome was used in calculating the HRD score (para [00342]).
Regarding claims 78-79, in the method of Abkevich Abkevich teaches that number of TAI regions >11 Mb in length with allelic imbalance that extend to one of the subtelomeres, but do not cross the centromere was used in calculating the HRD score (para [00342]).
Regarding claim 80, in the method of Abkevich Abkevich teaches that number of LST regions was the number of breakpoints between regions longer than 10 Mb (para [00342]). Abkevich teaches that the LSTs identified are somatic changes (para [0046] and [0048]: “LST refers to any somatic copy number…breakpoint”).
Regarding claim 83, in the method of Abkevich, by teaching that the method is performed using a panel that targets SNPs across the complete genome (para [00293]), Abkevich teaches that at least one pair of the human chromosomes are autosomes, given that only one pair of human chromosomes are sex chromosomes (see para [0002] or [0014]).
Regarding claims 91-92, in the method of Abkevich Abkevich teaches predicting response of a patient to DNA damaging agent (see instant claim 92) cisplatin based on HR Deficiency status (para [00352]; Table 18; see also [00153] and para [00160]).
Regarding claims 84-87, in the method of Abkevich, Abkevich teaches that the number of Indicator LOH Regions, Indicator TAI Regions and Indicator LST Regions are determined in at least 21 pairs of human chromosomes (para [00202]; see also the rejections of claims 75, 78, and 80 and regarding “Indicator” regions).
Abkevich teaches assaying 50,000 selected SNPs across the complete genome (para [00293]; instant claim 87; see also para [00285] and [0092-93]).
However, in the embodiment of determining HRD status in a BRCA deficient TNBC cell of a patient, Abkevich fails to explicitly teach performing the method on autosomes alone and a specific amount of loci per autosomal pair in the embodiment of a TNBC BRCA deficient patient/sample/cell.
Abkevich teaches excluding certain chromosomes from the analysis of HRD, such as the sex chromosomes if assessing males (para [0098]). Abkevich further teaches that it can be helpful to exclude chromosomes with unusually high levels of chromosomal aberrations in certain cancers when analyzing samples (para [0098]), and that separate cutoffs may be relevant to ploidy in BRCA intact and deficient samples (para [0049]).
Abkevich teaches determining at least 150 polymorphic genomic loci in at least 22 autosome pairs in an embodiment that allows predicting a response to a cancer treatment based on Indicator LOH Regions, Indicator TAI Regions, and Indicator LST Regions (para [00285]; instant claim 26).
It is noted that such a number of sites and effective density across the chromosomes is a matter of routine optimization. See MPEP 2144.05. Abkevich teaches optimization of SNP locations and supplemental sequencing at para [0092-93]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to utilize only autosomes in the method of Abkevich, motivated by the desire to utilize the method in males with breast cancer (as genetic males lack pairs of sex chromosomes) and/or if it were identified that X chromosomes contained unusually high levels of chromosomal aberrations in the cancer of interest (i.e., BRCA deficient TNBC), as taught by Abkevich. There would have been a strong expectation of success because this amounts to the application of a known technique of a known method and the artisan would be able to exclude a given chromosome from either the panel or the data analysis. See also omitting elements when the functions are not desired in MPEP 2144.04(II)(A).
Double Patenting
Claims 74-76, 78-80, 83-87, 91-92, and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. US 10,400,287 B2 in view of Abkevich (US 2014/0363521 A1; published 12/11/2014) and Telli (Telli ML, et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res. 2016 Aug 1;22(15):3764-73. Epub 2016 Mar 8; as cited in the IDS dated 12/06/2022).
Both sets of claims are directed to detecting, in a sample comprising a cancer cell, a test value equal to or derived from the sum of the number of LOH Regions, the number of TAI Regions, and the number of LST breakpoint Regions, and utilizing a reference value via sequenced DNA molecules.
‘287 further teaches the definition of Indicator LOH regions of instant claim 75, of TAI Regions of 78, and, in part, the definition of LST Regions of 80 (but fails to explicitly teach that the flanking regions are >10 Mb); determining in 15 pairs of chromosomes (but not explicitly autosomes); a density of SNPS (but fails to explicitly teach 5000 loci or a number in each autosomal pair). ‘287 teaches administering a treatment regime including the treatments of claims 91-92, but does not explicitly identify the patient as likely to respond.
‘287 teaches that the cancer cell harbors a deleterious mutation in BRCA1 or BRCA2. “BRCA1/2” (claim 1) of instant claim 74 may be interpreted as “BRCA1 or BRCA2”.
‘287 fails to teach applying the method to a TNBC cancer cell of a patient.
Any additional limitations of the claims of ‘287 are encompassed by the open claim language “comprising” found in the instant claims.
Abkevich rectifies the above deficiencies by teaching the (Indicator) LST Region definition; the number of loci both overall and per autosomal pair; utilizing the combined number to identify patients likely to respond; each of the instant claimed thresholds; and that the method may be applied to a BRCA deficient TNBC sample/patient, as has been cited in at least the 103 rejection above.
Abkevich further teaches that the HRD-combined score captured significant BRCA1/2 deficiency information not captured by clinical variables (para [00335]) and a threshold of >42 in the HRD-combined score was an effective predictor of pathologic complete response [to treatment] such that 0% of non-deficient patients had pCR whereas 28% of those with HRD status [using the threshold] obtained pCR (para [00347]; Table 13).
The motivating reference Telli further teaches that TNBC are not amendable to certain targets that may work for other subtypes (pg. 3764, Introduction, para 1). Telli teaches that sporadic TNBC may bear substantial similarities to BRCA1/2-mutated cancers, including DNA repair defects that might predispose to platinum sensitivity, and clinical trials have identified improvement in pathological response with the addition of platinum, but at the cost of increased toxicity (pg. 3764, Introduction, para 1). Telli further teaches that a predictive biomarker for platinum sensitivity would be helpful to personalize the use of platinum agents, restricting their use to those who would benefit while avoiding unnecessary toxicity for those who would not (pg. 3764, Introduction, para 1).
Telli teaches that some mutations in BRCA are deleterious (pg. 3765, Training set used to establish HRD score threshold), wherein the artisan would recognize that some mutations may not be deleterious.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine the method ‘287 with method of Abkevich add at least the step of identifying the cancer cell as being HRD deficient by comparing to a threshold, motivated by the desire to utilize an effective predictor of treatment response that may provide more information than clinical variables alone, as taught by Abkevich. It further would have been obvious, in light of Abkevich’s application to TNBC and the teaching of Telli, to utilize the method for BRCA mutated/deficient TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli, wherein the HRD status would enable differentiation between mutations likely to be truly deleterious and those that may have unknown significance, as suggested by Telli. There would be a strong expectation of success as both are directed toward assaying the same regions and represent the application of a known technique to a known method.
The all numeric limitations identified above in the 103 rejection are noted as matters of routine optimization for the same reasons. Any additional numeric difference between the instant claims and those of ‘287 is likewise identified as a matter of similar/overlapping ranges and routine optimization according to the same rationales.
Any additional limitations of the patented claims are encompassed by the open claim language “comprising” found in the instant claims.
Claims 74-76, 78-80, 83-87, 91-92, and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. US 12,421,555 B2 in view of Abkevich (US 2014/0363521 A1; published 12/11/2014) and Telli (Telli ML, et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res. 2016 Aug 1;22(15):3764-73. Epub 2016 Mar 8; as cited in the IDS dated 12/06/2022).
Both sets of claims are directed to determining, in a sample comprising a cancer cell, the number of LOH Regions, the number of TAI Regions, and the number of LST breakpoint Regions, in BRCA deficient cancers (claim 9) or breast cancers (3).
‘555 teaches the lengths for LST regions, TAI, and LST region lengths (claim 4); that the chromosomes are not sex chromosomes [i.e., are autosomes] (claims 1 and 6); and a density of SNP loci that requires above 150 loci for the smallest human autosome (claims 1 and 6).
‘555 fails to explicitly recite that the breast cancer cell may be TNBC; using the number of regions to establish an “HRD status” based on a particular threshold; at least 20 human chromosomes and 5000 loci each; and that the contacting is part of a sequencing.
Abkevich rectifies the above deficiencies by teaching that the patient may have BRCA deficient TNBC; the number of loci both overall and per autosomal pair; and utilizing the combined number consisting of the regions to identify patients likely to respond with a threshold of 42 or greater; and targeted sequencing, as has been cited in at least the 103 rejection above.
Abkevich further teaches that the HRD-combined score captured significant BRCA1/2 deficiency information not captured by clinical variables (para [00335]) and a threshold of >42 in the HRD-combined score was an effective predictor of pathologic complete response [to treatment] such that 0% of non-deficient patients had pCR whereas 28% of those with HRD status [using the threshold] obtained pCR (para [00347]; Table 13). Abkevich teaches capture probes are part of targeted sequencing (e.g., para [0091-92]; [00148]; [00304]; [00315]); that such target enrichment enables targeted sequencing decreases sequencing costs and reduces genomic complexity (para [00339]); and that such is a known alternative to microarray [another probe technology] for the analysis of such data (para [0091]).
The motivating reference Telli further teaches that TNBC are not amendable to certain targets that may work for other subtypes (pg. 3764, Introduction, para 1). Telli teaches that sporadic TNBC may bear substantial similarities to BRCA1/2-mutated cancers, including DNA repair defects that might predispose to platinum sensitivity, and clinical trials have identified improvement in pathological response with the addition of platinum, but at the cost of increased toxicity (pg. 3764, Introduction, para 1). Telli further teaches that a predictive biomarker for platinum sensitivity would be helpful to personalize the use of platinum agents, restricting their use to those who would benefit while avoiding unnecessary toxicity for those who would not (pg. 3764, Introduction, para 1).
Telli teaches that some mutations in BRCA are deleterious (pg. 3765, Training set used to establish HRD score threshold), wherein the artisan would recognize that some mutations may not be deleterious. Telli teaches that HRD status provides an improvement over clinical variables or BRCA1/2 mutation status (pg. 3772, para 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to combine the method ‘555 with method of Abkevich add at least the step of identifying the cancer cell as being HRD deficient by comparing to a threshold consisting of the combined number of regions, motivated by the desire to utilize an effective predictor of further treatment response that may provide more information than clinical variables alone, as taught by Abkevich. It further would have been obvious, in light of Abkevich’s application to BRCA deficient TNBC and the teachings of Telli, to utilize the method for BRCA mutated/deficient TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli, wherein the HRD status would enable differentiation between mutations likely to be truly deleterious and those that may have unknown significance, as suggested by Telli. It further would have been obvious to utilize sequencing, motivated by the desire to reduce genomic complexity, as taught by Abkevich; such is a known species of the genus of probe-based assays and as such represents the application of a known alternative. There would be a strong expectation of success as both are directed toward assaying the same regions and represent the application of a known technique to a known method.
The all numeric limitations identified above in the 103 rejection are noted as matters of routine optimization for the same reasons. Any additional numeric difference between the instant claims and those of ‘555 is likewise identified as a matter of similar/overlapping ranges and routine optimization according to the same rationales.
Any additional limitations of the patented claims are encompassed by the open claim language “comprising” found in the instant claims.
The following claims are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable the indicated claims of the listed copending Applications in view of Abkevich (US 2014/0363521 A1; published 12/11/2014) and Telli (Telli ML, et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res. 2016 Aug 1;22(15):3764-73. Epub 2016 Mar 8; as cited in the IDS dated 12/06/2022). These are provisional nonstatutory double patenting rejections.
Application No:
Instant claims rejected:
Rejected over claims:
Fails to recite:
Other notes:
17/353279
74-76, 78-92, and 94-95
59 and 61-67
• The cancer cell may be BRCA deficient TNBC; • ID’ing HRD status based on a test value and threshold; • Particular reference values/thresholds; • LST Region 10 Mb; • # of loci per autosome pair/loci overall; • # number of autosomes; • ID’ing a patient as a likely responder to particular therapies
• Broadly interpreted, ovarian, lung, etc. patients may comprise those whose TNBC, for example, has metastasized to the indicated sites
19/048611
74-76, 78-92, and 94-95
37-56
• The cancer cell may be TNBC (teaches breast cancer and BRCA deficiency); • ID’ing HRD status based on a test value and threshold; • Particular reference values/thresholds; • LST Region 10 Mb flanking regions; • # of loci per autosome pair; • # number of autosomes; • ID’ing a patient as a likely responder to particular therapies (claim 54 recites patient is candidate for platinum agents)
19/088496
74-76, 78-92, and 94-95
37-64
• The breast cancer cell may be TNBC and BRCA deficient; • ID’ing HRD status based on a test value and threshold; • Particular reference values/thresholds; • LST Region 10 Mb flanking regions; • # of loci per autosome pair; • # number of autosomes; • ID’ing a patient as a likely responder to particular therapies (claim 37 recites patient is candidate for chemotherapy; claim 39-40 recite instant claimed therapies)
All sets of claims are directed to a method of determining a number of LOH, TAI, and LST regions in a cancer cell of a patient, wherein the chromosomal aberrations are or may be of a minimum size and may be of a breast cancer where indicated above, and comprise methods where the regions are ascertained by sequencing.
Each of the co-pending applications fails to teach that the determined number of each may be utilized to identify an HRD status by combining the number of regions and comparing to a threshold, and fail to explicitly teach each of the other identified items in the table above.
Abkevich rectifies the above deficiencies by teaching the (Indicator) LST Region definition (including flanking region length); the number of loci both overall and per autosomal pair; utilizing the combined number to identify patients likely to respond; each of the instant claimed thresholds; that the test value may be derived from an arithmetic mean; identifying a patient as a responder to at least cisplatin; and that the method may be applied to a TNBC BRCA deficient sample/patient, as has been cited in at least the 103 rejection above.
Abkevich further teaches that that a sample has an "HRD signature" if such sample has a number of Indicator CA Regions exceeding a reference as described herein (para [0052]). Abkevich teaches that the HRD-combined score captured significant BRCA1/2 deficiency information not captured by clinical variables (para [00335]) and a threshold of >42 in the HRD-combined score was an effective predictor of pathologic complete response [to treatment] such that 0% of non-deficient patients had pCR whereas 28% of those with HRD status [using the threshold] obtained pCR (para [00347]; Table 13).
The motivating reference Telli further teaches that TNBC are not amendable to certain targets that may work for other subtypes (pg. 3764, Introduction, para 1). Telli teaches that sporadic TNBC may bear substantial similarities to BRCA1/2-mutated cancers, including DNA repair defects that might predispose to platinum sensitivity, and clinical trials have identified improvement in pathological response with the addition of platinum, but at the cost of increased toxicity (pg. 3764, Introduction, para 1). Telli further teaches that a predictive biomarker for platinum sensitivity would be helpful to personalize the use of platinum agents, restricting their use to those who would benefit while avoiding unnecessary toxicity for those who would not (pg. 3764, Introduction, para 1).
Telli teaches that some mutations in BRCA are deleterious (pg. 3765, Training set used to establish HRD score threshold), wherein the artisan would recognize that some mutations may not be deleterious. Telli teaches that HRD status provides an improvement over clinical variables or BRCA1/2 mutation status (pg. 3772, para 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to combine the method of the claims of any of the listed co-pending applications with method of Abkevich to add at least the step of identifying the cancer cell as being HRD deficient by comparing to a threshold, motivated by the desire to utilize an effective predictor of treatment response that may provide more information than clinical variables alone, as taught by Abkevich. It further would have been obvious, in light of Abkevich’s application to TNBC and the teaching of Telli, to utilize the method for TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli. It further would have been obvious, in light of Abkevich’s application to BRCA deficient TNBC and the teachings of Telli, to utilize the method for BRCA mutated/deficient TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli, wherein the HRD status would enable differentiation between mutations likely to be truly deleterious and those that may have unknown significance, as suggested by Telli. There would be a strong expectation of success as both are directed toward assaying the same regions and represent the application of a known technique to a known method.
The all numeric limitations identified above in the 103 rejection are noted as matters of routine optimization for the same reasons. Any additional numeric difference between the instant claims and those of the co-pending applications is likewise identified as a matter of similar/overlapping ranges and routine optimization according to the same rationales.
Any additional limitations of the co-pending claims are encompassed by the open claim language “comprising” found in the instant claims.
Response to Arguments
Applicant's arguments filed 1/15/2026 have been fully considered but they are not persuasive.
Regarding the 102 and 103 art rejections, Applicant argues that Abkevich does not anticipate the present claims at least because Abkevich allegedly does not expressly disclose “detecting homologous (HR) deficiency status of a BRCA deficient, triple negative breast cancer (TNBC) cell” or “detecting HR deficiency in the TNBC cell when the combined number of LOH regions, TAI regions, and LST regions is greater than 33”. Applicant further argues that Abkevich 2 does not disclose the limitations of the claim, and that the threshold is not a matter of routine optimization.
Contrary to arguments, Abkevich teaches detecting HR deficiency in samples from TNBC patients who are BRCA deficient with of 42 or greater (e.g., Fig. 15 and 16; para [00345] and [00349]). Low and high scoring is an “HRD status”, but para [00345] also makes clear that samples [comprising cells with TNBC] with scores > 42 have “high HRD”. Abkevich teaches referring to the detection of the status in the method for “a cell” of the cancer (entire document, e.g., Abstract, para [0045], [00153]).
The arguments over Abkevich 2 are moot as the citation has been updated refer to correctly refer to Abkevich, as in the 102, and 1207.03(a) makes clear that “lack of novelty is the epitome of obviousness”. However, for the sake of compact prosecution, the claim 74 has been rejected under both, wherein it is noted that at least the threshold is a matter of routine optimization. As described in further detail in the rejection, while applicants may have found the “exploratory” threshold of 33 or more that corresponds to the 1st percentile of TNBC that identified all BRCA deficient tumors in the sample (para [00390]), elsewhere in the document in para [0072], the wide ranges of thresholds of 5-50 are considered to be suitable for the invention, where 5 is even considered to be among the “preferabl[e]” options. Further, the artisan would understand that optimizing for, e.g., different values of sensitivity and specificity depending on application of the method may require different choices of threshold. Additionally, the counter point of ER+ breast cancer being suitable for use with a lower threshold does not preclude usefulness of the TNBC threshold, as the exemplary threshold recited is 1) right-unbounded interval that includes the TNBC range and 2) may be further optimized by increasing to, for example, reduce false positives. Thus, the threshold of 33 or greater corresponding to TNBC is not found to be a critical value for BRCA deficient TNBC.
Regarding the 101, Applicant argues that “detecting” the combined number of regions in at least one pair of human chromosomes cannot be practically achieved in the human mind; accordingly, the claims do not recite abstract ideas and are thus allegedly eligible under Step 2A. Applicant also argues that that claims must be considered as a whole and are allegedly non-obvious over at least Abkevich; given the alleged novelty, the claims should be considered patent eligible.
The instant claims require 33 regions of any the types of regions to achieve a “combined number”. LOH regions require “some minimum of consecutive loci” (para [0053]) but that is not appear to have been further defined. At minimum, this could be two. Even a larger targeted sequencing panel with processed calls of 5000 loci in at least 20 chromosomes corresponding to some number of greater than 33 loci could take time to review by hand but, contrary to Applicant’s argument, it would be achievable by a human within a period that is achievable by a human. It is noted that the courts have made clear that mental processes include those that can be completed with a pen and paper (e.g., from a print out of the processed sequencing results). See MPEP 2106.04(a)(2)(III).
Additionally, the claims are directed to mathematical calculations including algorithms and a natural phenomenon. Overcoming only the abstract idea of a mental process would be insufficient to integrate the claim as a whole into a practical application.
Further, regarding novelty, applicant points to the BRCA deficient TNBC sample type and the threshold of greater than 33 regions in the response to the 102 as rationale for overcoming the art rejections. As stated in MPEP2105.05(I), an inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). Even if the elements of the abstract ideas or the choice of the sample were found novel, which they were not, the courts have been clear that such is insufficient to amount to significantly more. See, also, Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015) regarding a novel sample being insufficient to furnish “significantly more”.
Having considered the claims as a whole, the elements of the abstract ideas and/or natural phenomenon combined with extra solution activity intended to provide data for the judicial exceptions do not amount to “significantly more”.
Conclusion
No claims are allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636